Drugs

Nano-drugs encased in liposomes could one day be used to treat neurological conditions like multiple sclerosis (MS), according to a new study published in the journal, PloS One. A liposome is a small, fat-soluble droplet that can contain a water soluble drug.

It is thought liposomes might be useful for treating neurological conditions because fat-soluble molecules can cross the blood-brain barrier, a blockade that protects the nervous system from the blood.

The researchers, based in Israel, used liposome-based nano-drugs to deliver drugs to the nervous system of mice that had been treated to have a form of experimental MS, called experimental autoimmune encephalomyelitis (EAE).

A common problem with conventional medications is that they are broken down too quickly by the body or they do not arrive at the site that they are intended to treat. Liposomal nano-drugs could help solve this problem by dissolving more slowly, and also by arriving at the site that requires treatment, specifically the nervous system. They could cross the blood-brain barrier, particularly useful for diseases that affect the brain and spinal cord. Furthermore, liposomal drug delivery could allow for more targeted drug delivery, requiring less active medication and resulting in fewer side-effects.

In the study, the researchers used two types of drugs, including methylprednisolone and Tempamine (TMN), delivered using the liposomal nano-method. According to their findings, “it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE [experimental MS].” The drugs reduced brain damage in the animal model, and also diminished movement problems that occur in these animals, which are similar to the movement problems found in MS. The medications also lasted longer in the blood before being broken down.

The authors further remarked that “the highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.”

Liposomal nano-drugs could provide a new way to deliver many old medications, improving the effectiveness and the delivery of existing drugs. Further studies in humans are of course needed.

Caitlin Dionne, RN, of Lahey Outpatient Centre in Massachusetts, and colleagues developed the MS Treatment Adherence Questionnaire in order to draw more honest answers about treatment compliance out of MS patients, noting that patient response to direct physician inquiry is often questionable.

The questionnaire included six questions related to DMT use: number of missed doses in four weeks; reason dose was missed; perceived side effects; ease of administration; and medication satisfaction. In the study, medication types were divided into subcutaneous or intramuscular (SC/IM), monthly IV injections, or oral DMTs.

Between October and November 2014, Dionne and colleagues collected data from 209 patients. Eighty nine patients (42.5 per cent) were on oral medication, 90 (43 per cent) on SC/IM, and 30 (14.5 per cent) on IV infusion. Among patients on oral DMTs, 45 per cent reported no missed doses, compared to 70.8 per cent of SC/IM and 93.3 per cent of IV infusion patients. Ease of taking the medication did not seem to affect treatment compliance, as 77 per cent, 60 per cent, and 33 per cent of patients on oral, IV, and SC/IM injections reported ease of use, respectively. Among patients taking oral and SC/IM injections, forgetfulness was among the top reasons for missing a dose.

As for how side effects may affect compliance, the majority of patients on IV infusion did not experience side effects, while 18.6 per cent of orals and 20.2 per cent of SC/IM patients reported them.

The authors speculated that side effect profiles related to oral DMTs may be at the centre of the reason for the poor compliance rates among oral users, despite oral DMTs' association with ease of use.

In another study, researchers from Washington, D.C.'s Veterans Affairs Medical Centre evaluated the effects of using a telehealth program on DMT compliance. The preliminary study, which followed 30 patients for six months, compared compliance rates with use of a MS-specific home automated telehealth system (MS HAT) to treatment as usual.

Patients — all who used SC/IM injections — who were assigned to the MS HAT group received text or email reminders to administer their medication through the system, which supports patient self-management, patient-provider communication, and patient education.

Although the MS HAT administration reminders was negatively correlated with syringe counts, the authors noted that as self-report adherence improved, the number of syringes collected increased. Overall, the results suggest that monitoring self-reported adherence through an automated teleheath system is a reliable method of assessing DMT adherence.

There has been an “alarming rise” in the cost of multiple sclerosis treatments over the past dozen years and the cost of these drugs increased at rates well beyond the overall growth in prescription drug prices, according to a new study.

Reporting on the Pharmalot medical blog, Ed Silverman says the study found costs for three older medicines, which were launched between 1993 and 1996, rose by statistically significant amounts after a new type of treatment became available in 2002.

And a similar pattern of rising costs continued as still newer medications were approved by regulators between 2010 and 2013, according to the study, which appears in the Neurology medical journal.

“Instead of dropping back or stabilising as newer drugs became available, the prices for older medicines continued to rise, notably for the older medications,” says Dennis Bourdette, who chairs the neurology department at Oregon Health & Science University and is a co-author of the study.

“You would think more new drugs would lower the rate of the increases, but that didn’t happen.”

The study also compared prices paid by Medicaid, the U.S. Department of Veterans Affairs and government purchasers in Canada, the U.K. and Australia. Although Medicaid receives discounts, the costs for the multiple sclerosis treatments were often more than 70 per cent lower in the other countries than what was paid by Medicaid. The VA, meanwhile, paid 36 per cent less, on average, than Medicaid.

The findings are the latest attempt to track rising costs for prescription medicines. Until now, the discussion has largely focused on treatments for hepatitis C, and cancer, as well some generic drugs. Bourdette says this is the first effort of its kind by neurologists to highlight the upward trend in multiple sclerosis drug costs.

The study examined pricing data for nine multiple sclerosis treatments – including older injectable medicines and newer oral drugs – between 1993 and 2013. The researchers also compared prices for the older drugs with another group of injectable medicines used to treat rheumatoid arthritis that were available during this time and found price hikes were much higher for the MS drugs.

More specifically, the study found three so-called first-generation MS treatments, which originally cost between $8,000 and $11,000 annually, now cost about $60,000. This worked out to an average increase of 21 per cent to 36 per cent annually for these three injectable drugs, which include Betaseron, which is sold by Bayer, Avonex, marketed by Biogen, and Copaxone, a big seller for Teva Pharmaceutical.

The cost increases for these drugs corresponded with the 2002 approval of Rebif, which is sold by Merck Serono, according to the study. And the trend continued with still newer oral drugs that were approved by the FDA between 2010 and 2013. These newer meds included Gilenya, which is marketed by Novartis, Aubagio, sold by Sanofi’s Genzyme unit, and Tecfidera, another Biogen medicine.

A Teva spokesman said pricing is competitive to other brand-name drugs and reflects investment to research, develop and sell a safe and effective product. A Bayer spokesman told Silverman that Betaseron pricing reflects its “value” and is “comparably” priced. A Biogen spokesman, meanwhile, said the drug maker provides discounts and revenues are used to fund research for new drugs.

Meanwhile, prices for the newer oral medications rose eight per cent to 17 per cent annually since their approvals over the past few years compared with overall prescription drug inflation of three-five per cent, according to the study.

“If the prices for the older drugs hadn’t been raised so dramatically, the newer drugs would have had a more difficult time pricing them as high as they did,” says Bourdette. “These companies didn’t have to price them at a lower level, because the prices for the older drugs were steadily being increased. What they’re doing is feeding off each other in terms of how the prices are set.”

A new study by the NYU Langone Medical Centre found almost 40 per cent of patients had some disease activity return when they stopped taking their meds. The findings, issued in a press release by the centre, have been presented at the American Academy of Neurology Annual Meeting held April 18-25, in Washington, D.C.

"Despite long periods of disease stability while taking medication, we found a large minority of patients who stopped experienced relapses or disability progression," said lead study author Ilya Kister, MD, an assistant professor of neurology at the NYU Langone Multiple Sclerosis Comprehensive Care Center.

"We need to identify situations when it is safe for patients with MS to stop taking these medications."

Little is known about MS disease progression after first-line, disease-modifying therapies are discontinued in clinically-stable patients.

Patients in the study were aged 40 and older, had experienced no relapses and reported stable disability progression (measured by EDSS scores) for at least 5 years, and had been taking medication for at least three years. Once medications were ceased, patients were followed for at least three years.

After discontinuing medication, 24 per cent of patients experienced a clinician-reported relapse, 32 per cent sustained three-month disability progression, and 10.6 per cent of patients recorded both relapses and disability progression.

Researchers found 77 patients - or 42 per cent - restarted medication after an average of 22 months. Restarting medication was associated with a 59 per cent risk reduction of disability progression.

"Decisions regarding stopping disease-modifying therapy may have implications for short and long-term prognosis. We know a lot about what happens when therapy is started, but we know very little about what happens when therapy is stopped", said Dr Kister.

Dr Kister and colleagues are now calling for a randomised trial of discontinuation of disease-modifying therapy to provide more evidence of when exactly it might be safe for patients to stop taking their medications.

Beta-interferons are the most widely prescribed drugs for patients with MS, but whether or not treatment with beta-interferons can delay the onset of secondary progressive MS onset has always been unclear.

The scientists took 794 patients with relapsing-remitting MS and compared them with a healthy control group. The outcome was gauged from the start of treatment with beta-interferons to confirmation of the onset of secondary-progressive MS.

In the published results, the researchers reported: “The median follow-up for the beta-interferon-treated, untreated contemporary and historical controls were 5.7, 3.7 and 7.3 years, and the proportions of patients reaching secondary progressive MS were 9.2 per cent, 11.8 per cent and 32.9 per cent, respectively. After adjustment for confounders, beta-interferon exposure was not associated with the risk of reaching secondary progressive MS when either the contemporary or the historical untreated cohorts were considered.”

The study concluded that, amongst patients with relapsing-remitting MS, use of beta-interferons was not associated with a delayed onset of secondary progressive MS.

Following on the heels of a Cochrane meta-analysis earlier in 2014, a new study finds that MS patients followed over 10 years have similar annualised relapse rates whether they take glatiramer acetate or one of the interferon betas.

No matter how you slice it, glatiramer acetate (GA) and the interferon betas (IFN-β) appear to be equally good treatment options for patients with relapsing-remitting multiple sclerosis (RRMS). A recent study from the Multiple Sclerosis Journal looked at 10 years of data on over 3,000 RRMS patients registered in MSBase, a global database of MS patients, and found that GA and IFN-β were similarly successful in reducing relapses (Kalincik et al., 2014). The study’s conclusions are similar to, though slightly different from, those of a Cochrane meta-analysis published in the summer of 2014 (La Mantia et al., 2014).

In the new study, researchers pulled data from MSBase on 3,326 RRMS patients who were using either IFN-β or GA as their first-ever disease-modifying therapy (DMT) for at least 6 months, and had started treatment within 10 years of their first symptom. To be included in the study, patients also had to have had at least one relapse recorded during the two years leading up to the start of their initial DMT. Each patient also had to have a minimal data set recording sex, age, date of first MS symptoms, dates of relapses, clinical MS score, their treatment center, and their baseline disability described by the Expanded Disability Status Scale.

The researchers looked at patients in four different treatment groups: IFN-β-1a intramuscular (IM), IFN-β-1a subcutaneous (SC), IFN-β-1b, and GA. They noted that, generally, patients treated with IFN-β-1a IM were less disabled at baseline than patients treated with the other interferons. Patients on GA were also generally older than patients on interferons. The researchers then paired each treatment group in six different head-to-head comparisons. The patients were also matched in clinical and demographic characteristics in each comparison.

For all treatments, the average annualised relapse rate (ARR) ranged from 0.38 to 0.56 relapses per year. The researchers noted that patients in the GA and IFN-β-1a SC groups had the lowest average ARR, with a relatively small range (0.15–0.16 relapses per year for GA and 0.09–0.1 relapses per year for IFN-β-1a SC).

Additionally, approximately one-third to one-half of all relapses were treated with steroids, and the researchers saw no significant differences in the efficacy of steroid treatment between the groups. The researchers also observed a significantly higher portion of relapse-free patients in the GA group compared to the IFN-β-1a IM and IFN-β-1b groups (p ≤ 0.02).

These findings match up with those of the Cochrane meta-analysis, which looked at a number of clinical outcomes, including relapse rate. In the Cochrane meta-analysis, the researchers found that in one head-to-head trial, patients on GA had a slightly better outcome in relapse rates at a 3-year follow-up. The Cochrane meta-analysis also found a number of small but significant variations in other outcome measures such as MRI data, but the new study did not look at the same outcomes.

The conclusions of both studies were that, by and large, GA and the IFN-βs are relatively similar in clinical outcome. None of the treatments showed major differences in accrued disability over time. It appears that GA and IFN-β-1a SC may be slightly superior in lowering ARR, but the data for all treatments are relatively limited.

The authors of the current study noted that they are “eagerly awaiting” similar reviews on newer treatment options.

For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists.

Eligible patients (relapsing-remitting course; ≥2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions.

Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year.

The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.

A growing body of evidence suggests that early control of disease activity in patients with multiple sclerosis (MS) plays a key role in preventing disability, prolonging the period of being active and engaged, and protecting quality of life.

The experts recommend initiation of these therapies as soon as possible following a diagnosis of relapsing MS. They also advise these agents for patients with a first clinical event and MRI features consistent with MS in whom other possible causes have been excluded, and for those with secondary progressive MS who continue to demonstrate clinical relapses and/or demonstrate inflammatory changes on MRI.

These recommendations, based on a comprehensive review of current evidence, appear in the paper,"The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence," produced by the Multiple Sclerosis Coalition, a group of MS organisations including the Accelerated Cure Project for Multiple Sclerosis, Can Do Multiple Sclerosis, the Consortium of Multiple Sclerosis Centers, the International Organization of Multiple Sclerosis Nurses, the Multiple Sclerosis Association of America, the Multiple Sclerosis Foundation, the National Multiple Sclerosis Society, and the United Spinal Association.

The document, written by a 5-member team and vetted by more than 50 experts in the field, has been endorsed by Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Not Carved In Stone

There's currently no algorithm for the order in which DMTs should be prescribed, said Kathleen Costello, MS, associate vice president clinical care, National Multiple Sclerosis Society, and one of the paper's authors. "It's not carved in stone which one you should start with, which one should be the next treatment or the 3rd treatment."

Because of this, said Costello, experts believe that "access needs to be available for all the therapies so decision-making on which therapy to use can be made on an individual basis." Factors to consider include patients' MRI findings, their clinical presentation, their risk tolerance, and their ability to adhere to a therapy.

Access to all the DMTs is all the more important as MS is a such a variable disease, added Rosalind Kalb, PhD, vice president, clinical care, advocacy, services and research department, also at the National Multiple Sclerosis Society. "Not only does the disease present and progress differently in different people, but individuals respond very differently for a variety of reasons to the available medications."

At the time of writing the document, 10 DMTs had been approved by the US Food and Drug Administration (FDA), all of which primarily target inflammation; however, none are fully effective in stopping MS disease activity or disease progression, the authors noted. An 11th agent (Plegridy, Biogen Idec Inc), a long-acting interferon β-1a, was just approved last week.

Although there are a growing number of approved treatment choices, patients sometimes have difficulty accessing them. In the past, it wasn't uncommon for providers to tell patients, "you don't need to be on that (β interferon); you're not 'bad enough' yet," said Costello. "But over the years, evidence has mounted showing that the better outcomes occur when treatment is initiated as early in the disease process as possible."

Early treatment can affect a range of disease factors, including delayed conversion to clinically definite MS, the document notes. The authors cited 4 phase 3 studies showing that in patients with clinically isolated syndrome, defined as the first episode of neurologic symptoms lasting at least 24 hours and caused by inflammation and demyelination in 1 or more sites in the central nervous system, conversion was delayed by about 45% at 2 to 3 years in patients taking glatiramer acetate or interferon compared with placebo.

As well, said the authors, early treatment may result in reduced relapse rates and slowed progression of disability. Reduced loss of mobility may improve the ability to carry out important activities of daily living.

No Catch-Up?

Such benefits, they added, "may not be equaled in those who start treatment later in the disease course," who may never "catch up" with those who start treatments immediately. However, a 10-year follow-up found no difference in disability outcomes between the early and delayed groups treated with intramuscular interferon β-1a, possibly indicating the delayed treatment group did catch up in this case.

"It remains to be determined the extent to which the older medications — and the newer medications for which we do not yet have any long-term data — impact longer-term disability outcomes for people with MS," the authors write.

The course of MS varies, with 85% to 90% of patients demonstrating a relapsing-remitting pattern at onset, which transitions over time in most untreated patients to a pattern of progressive worsening with few or no relapses (secondary progressive MS). The authors stressed that the optimal window for reducing long-term disability is during the early relapsing phase of the disease, with the goal being to slow the accumulation of lesion volume, decrease the number of relapses and prevent disability from both unresolved relapse and disease progression.

Patients without this relapsing pattern might demonstrate a steady progression of symptoms over time. This primary progressive disease presentation is generally diagnosed at an older age.

The paper includes an informative table listing the proposed mechanisms of action, adverse effects, and warnings/precautions of each MS agent. Another table shows the effect of self-injected, oral and intravenous agents on annualized relapse rate compared to placebo, and their effects on disability progression compared to placebo. A third table illustrates the effect of the various drugs on gadolinium-enhancing lesions and on new and enlarging T2 lesions.

An MS diagnosis often comes with other comorbidities. Some 60% of patients with MS will experience cognitive impairment, 36% to 54% will have a major depressive disorder, and up to 92% will endure substantial fatigue, which contributes to increased disability and reduction in quality of life.

There are an estimated 450,000 people with MS in the United States. Women are affected at least 2 to 3 times more than men, except for primary progressive MS, which is equally distributed between the sexes, and whites are affected more than other racial groups. Although some research shows a high incidence of MS farther away from the equator, recent studies have not demonstrated such a North-South gradient.

The Coalition will distribute the paper to delegates attending the upcoming joint ACTRIMS-ECTRIMS meeting in Boston, Massachusetts (September 10-13), and will post it on the Web sites of the participating MS groups. It will be updated at least every 6 months, something that is necessary because the MS treatment landscape changes so frequently, said Dr. Kalb.

Limited Therapy Options?

Asked for comment, Lily Jung Henson, MD, an MS neurologist, Swedish Medical Center, Seattle, Washington, said that the new paper nicely "summarizes the current level of evidence and knowledge around the management of MS."

"The fact that this is created by a coalition of MS groups stresses the consensus amongst MS specialists," she told Medscape Medical News.

The coalition's call for full access to DMTs is likely in response to some insurers trying to limit therapy options based on pricing, commented Dr. Jung Henson.

"A lot of the payers will, for example, insist that you use several of the interferons and glatiramer before you can use a more expensive pill. Or, patients have to fail several drugs before they can use the one that their neurologist thinks may be the best for them."

Although most MS neurologists do initiate treatment as soon as a diagnosis is made, "a lot of general neurologists are amazingly passive in their use of DMTs and their willingness to tolerate breakthrough disease without making a change," said Dr. Jung Henson.

Funding for the document was provided by member societies of the MS Coalition with no external support. Ms. Costello and Dr. Kalb have disclosed no relevant financial relationships. Dr. Jung Henson reports receiving honoraria from Biogen, Teva, EMD Serono, Pfizer, Novartis, and Genzyme and research funding from Biogen, Novartis, Genzyme, and Opexa.

Europe's drug safety regulator said multiple sclerosis treatments known as interferon beta need stronger label warnings because some patients treated with the drugs have suffered side effects affecting the kidney and other organs.

A spokeswoman for the European Medicines Agency said the label change would affect all countries in the European Union.

In a statement posted on its website on Wednesday, German regulator BfArM said cases of a condition called thrombotic microangiopathy, or TMA, have occurred after weeks or even several years of treatment with interferon beta, some of them fatal.

Interferon beta drugs, which are injected, have been in use for more than 10 years.

TMA affects the kidney and a range of other organs, and BfArM said its symptoms included high blood pressure, fever, disorientation, impaired kidney function and a low count of coagulation cells in the blood.

It added that patients diagnosed with TMA should be taken off interferon beta and should be treated immediately.

Cases of another condition, nephrotic syndrome, have also been reported among interferon beta users and will be included in the label change, the European and German regulators said, again without saying how many patients could be affected.

A new comprehensive report on the safety of MS drugs may have doctors rethinking their recommendations.

The results are in, and according to a recent report comparing the safety records of all multiple sclerosis (MS) drugs on the market, Tecfidera took the top safety prize. The report reveals that newer MS drugs received high marks for safety, while older interferon drugs had more reported side effects.

California-based health informatics company AdverseEvents analyzed side effects data from the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) database. The FDA asks that doctors, consumers, and drugmakers report any serious negative health events they or their patients experience while taking an FDA-approved drug.

Using a formula called the “reporting odds ratio” (ROR), analysts compare how often an adverse event (AE) has been reported, regardless of drug, to how often the event has been reported for a specific drug in the FAERS database. This helps safety professionals identify AE and drug pairs with a higher than usual occurrence of a particular side effect, sending up a red flag.

Because the ROR is a ratio that is not affected by length of time a drug has been on the market, the analysts at AdverseEvents were able to compare the oldest MS drugs with the newest and compile accurate results, giving each drug an “RxScore.”

So, comparing the AEs reported for all MS drugs only during the time period since Tecfidera won approval did not affect the outcome, said Keith Hoffman, Vice President of Scientific Affairs at AdverseEvents, in an interview with Healthline. “We have completed that time comparison with other drug classes many times and the overall results stayed the same.”

A Few Bad Apples

The RxScore scale ranges from 0 to 100, with higher numbers indicating a greater risk of adverse events. Avonex, Rebif and Betaseron, all interferons, had the worst safety records, with scores between 53 and 55. Copaxone had the fourth highest score at 47.4.

Betaseron had the highest ratio for reports of disability or death, while Avonex users were hospitalized due to AEs the most often.

People taking Avonex reported more malignant tumors, breast cancer diagnoses, and flu-like symptoms than those taking other drugs, while Betaseron users reported more heart attacks, bacterial infections, and liver problems.

Rebif received the worst RxScore, with a higher proportion of negative events including suicidal behavior, optic nerve inflammation, and cancers of the female reproductive system.

Copaxone fared worst for life-threatening allergic reactions and psychiatric symptoms. But Copaxone, FDA-approved in 1996, scored best on measures of several side effects, including cognitive disorders and flu-like symptoms, making it the safest of the older first-line MS drugs.

The Best of the Bunch Tecfidera attained the lowest RxScore of 33 and the lowest ROR of life-threatening events, hospitalizations, disability, or death. It also scored lowest for everything from bacterial infections to optic nerve disorders and liver problems. Overall, Tecfidera had the lowest ROR for 24 out of the 58 side effects the researchers studied.

Gilenya scored second best at 39.4, but users had more cardiac-related AEs, including lowered heart rate, and the drug also scored the worst for vision disorders and skin cancers. Gilenya, FDA-approved in 2010, did not hold the lowest score for any reported AEs.

Aubagio, with the same RxScore as Gilenya, had the highest number of reports of diarrhea, but that’s the only side effect for which it scored the highest, making it among the safest of the MS therapies.

Tysabri scored relatively well but had the highest ROR for cognitive disorders, JC virus positive tests, and secondary progressive MS. The report also concluded that the relationship between Tysabri and primary multifocaleukoencephalothopy, or PML, a rare and deadly brain infection, was confirmed.

Extavia had the worst safety score of any of the new MS drugs at 44.9, and users suffered the most depression, falls, headaches, and injection site reactions.

What Does It All Mean?

The FAERS database only examines side effects, not effectiveness. And it cannot predict side effects that may emerge over time.

“We are limited by what is recorded into FAERS,” Hoffman points out. “If a safety concern takes years to manifest after a drug’s approval we will not see those reports until they are filed.”

Although this report is an effective tool for neurologists recommending drugs to their patients, doctors must also consider each drug's effectiveness. Does it have a track record for reducing relapses, preventing disability, or protecting neurons?

Weighing the risks and benefits is a crucial process when selecting a drug for an MS patient. And everyone’s MS experience is different. Nobody will have all of the reported side effects—or all of the benefits.

The reductions in brain volume often seen in patients with chronic relapsing–remitting multiple sclerosis may be reduced by treatment with interferon beta-1a, though treatment may be affected by the patient’s immunologic status, according to data presented by Michael G. Dwyer, PhD, at the 2014 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Sixth Cooperative Meeting with Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Dwyer is an assistant professor of neurology in the Department of Neurology at the University of Buffalo School of Medicine and Biomedical Sciences, and the technical imaging director of the Buffalo Neuroimaging Analysis Center, Buffalo, NY.

According to Dwyer, chronic relapsing-remitting multiple sclerosis (RRMS) progression is often associated with decreased brain volume. “We know there are volume changes, but we don’t have a ‘smoking gun,’” he said.

In the study write-up, the authors noted that “Over the short term, brain volume may change, via inflammation-related hydrodynamic changes, which subside following anti-inflammatory therapy,” known as pseudoatrophy.

Dwyer presented data from a study, titled “Relapsing-Remitting Multiple Sclerosis Treated with Interferon Beta-1a: Immunologic and Short-term Volume Changes,” that compared percent brain volume change between 23 patients with relapsing-remitting multiple sclerosis who were treated for 24 weeks with subcutaneous injections of interferon beta-1a three times per week, and 15 healthy controls.

Researchers assessed percent brain volume change from baseline to month 3, from month 3 to month 6, and from baseline to month 6 and compared differences both within and between groups. The study found that the percent brain volume change between baseline and 3 months was -0.95% (SD= 1.712%) among patients with relapsing-remitting multiple sclerosis (P=0.03) and 0.24% (SD 1.068%) among healthy controls (P=0.36).

The difference was significant between groups (P=0.02).

However, the researchers found no significant difference in percent brain volume change within or between either group from months 3 to 6, or from baseline to month 6.

Treatment with subcutaneous interferon beta-1a was associated with reduced brain volume over the first 3 months of treatment, but there were no differences in brain volume seen in treated patients from month 3 to month 6, or from baseline to month 6.

The authors noted “the correlation between decreased percentage of CD4+ T cells producing inflammatory IL-17F and volume reduction is supportive of an early anti-inflammatory effect” of treatment with subcutaneous interferon beta-1a.

Although there are a host of options available for treating multiple sclerosis (MS), the practicing clinician will find relatively little guidance to help optimise treatment for individual patients, according to the University of California-San Francisco’s Bruce Cree, MD, PhD. He presented a review of treatment choices and strategies at the American Academy of Neurology annual conference on April 30, 2014, in Philadelphia, PA

In framing choices for clinicians, Cree noted that strategies for initiating treatment may vary; further, there is a dearth of good “switch” studies, which would give guidance about changing MS treatment when a patient is not tolerating a medication or not responding to treatment. However, a thorough understanding of the efficacy and safety profiles of some of the newer choices among MS drugs can help with logical and patient-centered decision making.

Cree began the discussion by proposing that initial treatment planning could be guided by one of two strategies. The first would involve a tiered strategy, beginning with medications generally accepted as safer, but which may be less efficacious. Treatment response can be assessed by relapse incidence, disability progression, and changes in imaging findings. An alternate strategy, reviewed below, would try for maximal efficacy from the initial time of treatment forward.

Medications generally considered to be “first-tier” would be the interferons, along with glatiramer acetate (Copaxone), according to Cree. Some clinicians might also place fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) in the first-line category. The common side effects associated with interferon therapy are significant but well known, and clinicians can be vigilant for worsening or serious effects. Similarly, glatiramer acetate can cause post-injection site reactions, flushing, and chest pain, all of which can be anticipated and monitored.

For some clinicians and some patients, fingolimod’s safety profile might place it in the second-line column. Mitoxantrone (Novantrone) and natalizumab (Tysabri), also generally considered less safe, would similarly be considered second-line therapy. This tiered approach has the advantage of being easily understood by patients and families, and uses proven agents with well-known safety and side effect profiles. On the other hand, Cree said this tiered treatment strategy does not take individual patient needs into account. For many patients, natalizumab will be considered: it has been proven effective, with a 68-70% reduction in relative risk (RR) of relapse and a 42-54% reduction in hazard ratio (HR) for disability progression. However, individuals who are positive for the John Cunningham virus (JCV) antibody are at increased risk for progressive multifocal leukoencephalopathy (PML), a potentially devastating complication. About 50% of individuals carry the JCV antibody, and their risk for PML may be particularly high if they have had prior immunosuppression.

Fingolimod, another effective treatment, yields an overall 54% reduction in RR of relapse and a 30% reduced HR for disability progression. There is no clear risk of PML associated with this treatment, so it can be used in JCV seropositive individuals. However, bradyarrhythmias can result, so a baseline EKG, along with vital sign monitoring and an EKG at dosing and six hours after administration are recommended. The risk of undetected macular edema can be mitigated by obtaining a baseline ophthalmologic exam with follow-up exams every 3-4 months. Spirometry at similar intervals can monitor lung function. The risk of infection can be reduced by providing varicella zoster immunization before treatment initiation, avoiding concurrent steroid use when possible, and avoiding administration of live attenuated vaccines.

Among the oral agents, teriflunomide is an option for many patients. It carries an overall 32% reduction in RR of relapse and a 30% decrease in HR for disability progression. Hepatic and renal function must be monitored, and patients should be counseled about risk for neuropathy, alopecia, and hypertension. Blood pressure should be monitored regularly. Teriflunomide is pregnancy category X, with teratogenicity shown in animal models (though available human data do not show elevated risk of adverse pregnancy outcomes). Clinicians should provide pretreatment counseling to avoid pregnancy; if pregnancy should occur, the drug should be eliminated immediately with cholestyramine or activated charcoal.

Dimethyl fumarate is taken as a twice-daily capsule, and shows an overall 53% decrease in RR of relapse and a 38% reduction in HR for disability progression. There is a theoretic risk of PML with this medication, so checking JCV serology before starting treatment is recommended. Baseline and follow-up CBC and liver function testing can monitor for the risk of elevated liver enzymes and lymphopenia. GI side effects are common; flushing can be minimized with the co-administration of aspirin.

Returning to treatment strategies, Cree proposed considering a “maximal efficacy” rather than a tiered approach. In this model, the most efficacious treatment should be the first one considered, if patient characteristics allow. Natalizumab might then be the first drug considered for JCV-negative individuals. Fingolimod would also be an initial choice, with efficacy arguably superior to the interferons. Cree also made the point that oral medications are better tolerated and may result in better adherence than self-injectibles, another important consideration. The maximal efficacy approach may allow for early disease modification, reducing inflammation initially, with later transition to a “maintenance” phase with what are now considered first-line treatments. This treatment strategy, with initial use of potentially cytotoxic medications to modify disease course, borrows from oncology. Cree encouraged industry and academia to conduct more long-term observational studies comparing the two approaches; in this way, clinicians can be guided to help patients reach the best outcomes.

Beta2-adrenergic agonist use and the risk of multiple sclerosis: a total population-based case-control study.

Abstract

OBJECTIVE: The aim of this study was to investigate whether the use of fenoterol, a beta2-adrenergic agonist, was associated with multiple sclerosis (MS) risk by conducting a total population-based case-control study in Taiwan.

METHODS: A total of 578 patients with newly diagnosed MS who had a severely disabling disease (SDD) certificate between January 1, 2002 and December 1, 2008 comprised the case group. These cases were compared with 2890 gender-, age-, residence-, and insurance premium-matched controls. Fenoterol use was analyzed using a conditional logistic regression model that controlled for asthma, chronic obstructive pulmonary disease (COPD), salbutamol and steroid use.

RESULTS: Compared with the group of people who did not use fenoterol, the adjusted odds ratios were 0.67 (95% confidence interval (CI) = 0.48-0.93, p = 0.016) for the group prescribed fenoterol below 2.25 cumulative defined daily dose (cDDD) and 0.49 (95% CI = 0.33-0.71, p < 0.001) for the group with a cumulative fenoterol use of more than 2.25 cDDD. The dose-response relationship was similar within the non-asthma patients. The associations were similar between males and females, but differences between age groups were observed.

CONCLUSIONS: The results of this study suggest that fenoterol use may reduce the risk of MS.

Data sources for MS research are numerous but rarely provide an objective measure of drug therapy compliance coupled with patient-reported health outcomes. The objective of this paper is to describe the methods and baseline characteristics of the Therapy Optimisation in MS (TOP MS) study designed to investigate the relationship between disease-modifying therapy compliance and health outcomes.

Methods: TOP MS was designed as a prospective, observational, nationwide patient-focused study using an internet portal for data entry.

The protocol was reviewed and approved by Sterling IRB. The study was registered with ClinicalTrials.gov.

It captured structured survey data monthly from MS patients recruited by specialty pharmacies. Data collection included the clinical characteristics of MS such as MS relapses.

Disability, quality of life and work productivity and activity impairment were assessed quarterly with well-validated scales. When events like severe fatigue or new or worsening depression were reported, feedback was provided to treating physicians.

The therapy compliance measure was derived from pharmacy drug shipment records uploaded to the study database. The data presented in this paper use descriptive statistics.

The mean age of the sample was 49 years, 80.4% were female, 89.9% were Caucasian and 55.7% were employed full or part time. Mean time since first symptoms was 11.5 years; mean duration since diagnosis was 9.5 years.

Patient-reported EDSS was 3.5; 72.2% had a relapsing-remitting disease course. The most commonly reported symptoms at the time of enrollment were fatigue (74.7%), impaired coordination or balance (61.8%) and numbness and tingling (61.2%).

Conclusion: Demographic and clinical characteristics of the TOP MS sample at enrollment are consistent with other community-based MS samples, and the sample appears to be representative of DMT users in the US. TOP MS data can be used to explore the associations between disease-modifying therapy compliance and health outcomes.Trial registration: ClinicalTrials.gov (NCT00819000).

Objectives: In 2002, the UK's National Institute for Health and Care Excellence concluded that the multiple sclerosis (MS) disease modifying therapies; interferon-β and glatiramer acetate, were not cost effective over the short term but recognised that reducing disability over the longer term might dramatically improve the cost effectiveness. The UK Risk-sharing Scheme (RSS) was established to ensure cost-effective provision by prospectively collecting disability-related data from UK-treated patients with MS and comparing findings to a natural history (untreated) cohort. However, deficiencies were found in the originally selected untreated cohort and the resulting analytical approach. This study aims to identify a more suitable natural history cohort and to develop a robust analytical approach using the new cohort.

Design: The Scientific Advisory Group, recommended the British Columbia Multiple Sclerosis (BCMS) database, Canada, as providing a more suitable natural history comparator cohort. Transition probabilities were derived and different Markov models (discrete and continuous) with and without baseline covariates were applied.

Setting: MS clinics in Canada and the UK.

Participants: From the BCMS database, 898 ‘untreated’ patients with MS considered eligible for drug treatment based on the UK's Association of British Neurologists criteria.

Outcome measure: The predicted Expanded Disability Status Scale (EDSS) score was collected and assessed for goodness of fit when compared with actual outcome.

Results: The BCMS untreated cohort contributed 7335 EDSS scores over a median 6.4?years (6357 EDSS ‘transitions’ recorded at consecutive visits) during the period 1980–1995. A continuous Markov model with ‘onset age’ as a binary covariate was deemed the most suitable model for future RSS analysis.

Conclusions: A new untreated MS cohort from British Columbia has been selected and will be modelled using a continuous Markov model with onset age as a baseline covariate. This approach will now be applied to the treated UK RSS MS cohort for future price adjustment calculations.

Patients who received early and consistent disease modifying treatment at the first signs of multiple sclerosis – often called clinically isolated syndrome (CIS) – appeared to have a slower progression to disability than patients who were treated mainly for additional MS exacerbations, researchers reported here.

Over a 12-month period, patients treated 50% to 80% of the time following the first CIS event reduced their risk of progression -- as measured by the Expanded Disability Status Scale score -- by 45% compared with patients who received disease-modifying treatments less than 50% of the time or not at all (95% CI 0.39-0.79, P=0.001), and patients treated for more than 80% of the time following diagnosis reduced their risk of disability progression by 68% (95% CI 0.22-0.49, P<0.001), said Vilija Jokubaitis. PhD, post-doctoral fellow in neuroimmunology at the University of Melbourne.

"What was very interesting about this finding was that the patients who appeared to be worse after their CIS and MRI evaluation and who were treated early, did better than patients whose treatment was delayed," she said in her oral Young Investigators report at the annual meeting of the European Association for the Treatment and Research In Multiple Sclerosis.

About three-fourths of these patients were classified on the basis of T2 lesion enhancement as having relapsing-remitting multiple sclerosis at first treatment. Jokubaitis suggested that because their initial examinations looked worse, the patients were treated more aggressively, and that appeared to have long-term benefits in preventing progression.

"Study after study has shown that early treatment with disease-modifying drugs benefits patients with CIS," said Margaret Burnett, MD, assistant clinical professor of neurology and pathology at the University of Southern California in Los Angeles.

"It kills me that some places still are not treating CIS," she told MedPage Today. "These findings presented here are corroborating evidence that we should be treating CIS and we should make every effort to provide continuous treatment."

In the study, Jokubaitis and colleagues reviewed data involving 1,989 patients for whom complete records were available. The patients had a combined 6,724 years of follow-up with a median follow-up of 3 years per patient – ranging from 9 months to 9.9 years.

Of those patients, 1,339 were treated with disease-modifying agents, either interferon-based products or glatiramer acetate (Copaxone). The researchers included 307 patients who had sustained disability progression over 12 months.

The goal of the study was to determine predictors of progression, and the investigators found that advancing age was a weak prognosticator of disability progression – a 17% increased risk per decade (P=0.006). They also found that pyramidal system dysfunction was a strong predictor of disability progression – with higher imaging pathology translating to a 46% increased risk of disease progression (P=0.008).

Jokubaitis acknowledged that teasing out how treatment affected outcomes was confounded by the fact that sicker patients at diagnosis were more likely to be treated early and consistently, which helped them avoid disease progression.

She and her colleagues did scrutinize the different disease-modifying agents used in the study, but found all of them were successful in delaying progression and none appeared significantly better than the other, although treatment with glatiramer acetate approached significance compared with interferon-beta 1a intramuscular injection (P=0.052) in an ad-hoc analysis.

Co-Author Marie Trojano, MD, professor of neurology at the University of Bari in Italy, and president of ECTRIMS, told MedPage Today that concerns that clinically isolated syndromes might not be true multiple sclerosis should be discarded. "There really should not be a disease called CIS. Imaging scans can tell us these events are early multiple sclerosis."